The Efficacy and Safety of CKD516 Combined With Durvalumab in Patient Refractory Solid Tumors

A Phase I Study to Determine the Efficacy and Safety of CKD-516 Tablet Combined With Durvalumab(MEDI4736) in Patient Refractory Solid Tumors

This is a single center, open-label, nonrandomized, Phase 1b, dose-escalation study designed to determine maximum tolerated dose (MTD) of CKD-516 in combination with durvalumab and evaluate the safety and tolerability profile, efficacy of CKD-516 and durvalumab treatment.

Dose Escalation cohort (Stage 1) With traditional 3+3 dose-escalation design, the safety, tolerability, and pharmacokinetics of CKD-516 in combination with durvalumab will be evaluated. Three dose levels of CKD-516 (9, 11, 13 mg/m2) will be investigated in combination with durvalumab 1,500 mg. At each dose level, 3 to 6 patients will be enrolled. After completion of 1 cycle of treatment of all patients in each dose level, decision for enrollment of subjects for next dose level will be decided after review of safety profile by safety review (SRM). Extension cohort (Stage 2) Stage 2 is an exploratory study for the evaluation of the efficacy of recommended phase 2 dose (RP2D) of CKD-516 in the combination with Durvalumab in patients with specific types of solid tumors (listed below). Arm 1: Colorectal cancer (CRC) Arm 2: Other cancer (Pancreatic cancer, Cholangiocarcinoma, Stomach cancer, Esophageal cancer)

Stage 1 : dose escalation durvalumab (1500 mg Q4W) plus CKD-516 at dose levels (9, 11, or 13 mg/m2) Stage 2 : durvalumab (1500 mg Q4W) plus CKD-516 at recommended phase 2 dose

Stage 1 : dose escalation durvalumab (1500 mg Q4W) in combination with CKD-516 at 1 of 3 planned dose levels (9, 11, or 13 mg/m2 twice a week for 3 weeks in each cycle, Q4W). Stage 2 : durvalumab (1500 mg Q4W) in combination with CKD-516 at recommended phase 2 dose (twice a week for 3 weeks in each cycle, Q4W).

- Progression free survival will be measured from the start of treatment with investigational product until the first documentation of disease progression or death due to any cause, whichever occurs first.

the duration from the first documentation of objective response to the first documented disease progression or death due to any cause, whichever occurs first

Inclusion Criteria: Stage 1; Dose escalation cohort: Patients with histopathologically confirmed various tumors including CRC, pancreatic cancer, cholangiocarcinoma, stomach cancer, and esophageal cancer, with measurable or non-measurable disease as determined by RECIST version 1.1, who have progressed despite standard therapy or are intolerant of standard therapy, or for whom no standard therapy exists. Age > 20 years at time of study entry Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Must have a life expectancy of at least 12 weeks Body weight >30 kg Adequate normal organ and marrow function as defined below: Haemoglobin ≥9.0 g/dL Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm3) Platelet count ≥75 x 109/L (>75,000 per mm3) Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician) AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN All patients must provide and FFPE tumor sample for tissue-based IHC staining to determine TIL and other correlatives. Tumor tissue can be either from the primary tumor or metastatic biopsy. If tumor tissue is unavailable, samples should be collected with biopsy before treatment. Archived tumor specimens of ≤3 years are acceptable for IHC. Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy to the institutions' guidelines. Patients must be willing to undergo a new tumor biopsy at screening and during therapy on this study. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Extension Cohorts (Stage 2) 1. Patients with GI cancers confirmed by histopathology or cytologic examination including CRC, pancreatic cancer, cholangiocarcinoma, stomach cancer, and esophageal cancer. 2~11. same above Exclusion Criteria: Patients with a history of hypersensitivity to the components of study drugs Prior exposure to any immunotherapy Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) ≤ 14 days prior to the first dose of study drug (in case of nitrosoureas and/or mitomycin, within 6 weeks before study participation) Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. (in case of VATS and/or ONC surgery, within 2 weeks before study participation) History of allogenic organ transplantation. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: Patients with vitiligo or alopecia Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Patients without active disease in the last 5 years may be included but only after consultation with the study physician Patients with celiac disease controlled by diet alone Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events or compromise the ability of the patient to give written informed consent History of another primary malignancy except for Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease History of active primary immunodeficiency Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B, and hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients with chronic hepatitis B, confirmed by the presence of anti-HBc, receiving antiviral therapy may be enrolled if the disese is controlled for at least 1 month prior to screening. Controlled hepatitis is defined as serum HBV DNA < 2,000 IU/mL by polymerase chain reaction (PCR). Patients with controlled hepatitis B must remain on antiviral therapy, per institutional practice, to ensure adequate viral suppression, during the study. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. History of venous thrombosis within the past 3 months prior to the scheduled first dose of study treatment Presence of acute coronary syndrome including myocardial infarction or unstable angina pectoris, other arterial thrombotic event including cerebrovascular accident or transient ischemic attack or stroke within the past 6 months prior to the scheduled first dose of study treatment New York Heart Association (NYHA) Class II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or uncontrolled hypertension(more than 160 mmHg systolic and/or more than 100 mmHg diastolic, despite appropriate antihypertensive medication Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.

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